Theodora Tzakri

• Nowadays, life expectancy is consistently rising, and the population of older people is growing exponentially worldwide. Even though older people are the main end users of drug products, yet they are significantly underrepresented in clinical trials focused on new drug entities. Currently, clinical trials predominantly involve younger adults, overlooking the physiological changes relevant to oral drug absorption in older individuals. This exclusion is concerning given the incidence of changes in the physiology of the aging gastrointestinal tract that may impact gastric emptying and motility and therefore oral drug absorption. In particular, gastric emptying of water is an important parameter for oral biopharmaceutics since clinical bioavailability and bioequivalence studies typically include the ingestion of oral formulations with a glass of water under fasted and fed state conditions. Even though plentiful of studies have investigated gastric water emptying in younger volunteers, this is not the case in older people. Data from gastric emptying studies in older people is limited and contradictory, whereas the occurrence of the Magenstrasse in the fed state in older individuals has been up to date not investigated. A patient-centred approach to drug development is crucial, ensuring that medications are appropriately tested and optimized for the physiological needs of older patients, particularly under varying prandial conditions. To close these knowledge gaps, in this work the gastric emptying rate of water was assessed using the indirect method of salivary caffeine kinetics. This non-invasive method was further advanced by the development of a novel formulation containing the salivary marker caffeine to increase its suitability for use in older people, and therefore patient acceptability and compliance with the study procedure. Summarized, the results of this thesis can be outlined as follows: First, an extensive literature review was conducted to gather all relevant information regarding previous clinical studies investigating age-dependent changes in the physiological characteristics of the gastrointestinal tract relevant to oral drug absorption. Results from gastric emptying studies in older individuals are controversial, mainly because of different methods, study designs, and measurement parameters used. Second, a novel rapid-disintegrating and dissolving tablet formulation containing caffeine was developed to advance the salivary caffeine method to be applied in the study including older individuals. According to this method, gastric water emptying is indirectly assessed by evaluating the pharmacokinetic profile of salivary caffeine concentrations. The new tablet formulation was successfully validated against the previous formulation (i.e. the ice capsule) in healthy young adults in a clinical study under fasted and fed state conditions. Third, the impact of advanced age in gastric water emptying was investigated with the aforementioned method. Healthy older and healthy younger volunteers were recruited in a clinical study in fasted (after overnight fasting) and fed state (after the intake of a low-fat breakfast). Differences between gastric emptying of the two population groups was evaluated indirectly by evaluating the AUC ratios (%) of salivary caffeine concentrations in specific time segments. No significant difference could be proven (p > 0.05), which indicates that gastric water emptying remains unchanged in relation to healthy aging. These results provide a better understanding in oral drug absorption in older individuals and facilitate the drug development of oral drug products specified to the needs of the aging population. However, taking into consideration the high proportion of older people affected by multimorbidity, polypharmacy and frailty, we could surely say that these outcomes are not representative of the whole cohort of older individuals. As the aging population is very heterogeneous, a useful approach would be to investigate the impact of these factors by creating subgroups of this population and studying specific parameters separately (e.g. older individuals with multimorbidity versus healthy older individuals). Given these factors, future studies are needed to better understand how they may affect gastric emptying rates and motility. This will lead to a better understanding of the underlying mechanism of any changes observed in oral drug absorption and disposition in older adults, and therefore improve oral drug development.